JPS60174782A - Separation of scopolamine and hyoscyamine - Google Patents

Abstract

PURPOSE:To separate and to obtain highly the titled compound useful as a raw material for drugs such as an antispasmodic, etc. by one treatment by easy operation, by bringing a mixed extract of scopolamine and hyoscyamine to a specific adsorbent under specific conditions. CONSTITUTION:A plant extract containing scopolamine (compound shown by the formula I ) and hyoscyamine (compound shown by the formula II) is brought into contact with a synthetic high polymer adsorbent (e.g., a nonpolar or middle polar adsorbent such as Amberlite XAD-2, etc.) having a macro-structure of network in a state of aqueous solution at <=7.0pH, scopolamine is collected from a part not adsorbing it and a part eluting it by water washing, and hyoscyamine is obtained by eluting it adsorbed on the adsorbent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for separating scopolamine and hyoscyamine, which are present in a mixture, into individual compounds.

Both scopolamine and hyoscyamine are compounds belonging to tropane alkaloids, and their structural formulas and molecular weights are as follows.

Scopolamine C, H2, NO, molecular weight 303.35 Hyoscyamine C, H2, No, molecular weight 289.3 Neuroleptics (antispasmodics), eye drops,
It is an important pharmaceutical raw material used in alkaloid anesthetics in combination with opium alkaloids.

Scopolamine and hyoscyamine are available from Duboisi
a myopo-roides, Duboisia
D
atura mefel, Datura alba,
Plants of the genus DaLura such as DaLura +*efelfolinu+a, and other ALropa belladonna
(Belladonna), ) Iyoscyamus n1Be
r (henbane), 5col+oliu jalon+i
It is contained in various Solanaceae plants such as ca (Hashiridokoro), and what is extracted and purified from these plants is
” It is used as a raw material for the production of derivatives. The most commonly used extraction raw material for Azusa-dong is the Zuboisha plant, whose dried leaves contain 0.5 to 2.5% scopolamine.
They each contain about 1 to 1.0% of hyoscyamine.

For extraction of plants containing scopolamine and hyoscyamine, neutral to acidic water or a mixture of water and a wood-friendly organic solvent such as methanol or ether is usually used.

When this type of extraction is performed, scopolamine and hyoscyamine are extracted together, but since the subcompounds have different pharmacology, efficacy, side effects, etc. as pharmaceuticals, are they not used as a mixture? It is necessary to perform a process to separate sub-compounds. A typical conventional separation method is to separate an aqueous solution containing scopolamine and hyoscyamine with an organic solvent such as chloroform or ether on the aqueous solution side, as described in the Japanese Pharmacopoeia 10th revised edition commentary
Countercurrent distribution is performed while adjusting H, and fractionation is performed by utilizing the difference in the distribution ratio of subcompounds to the solvent. However, in this method, the difference in the distribution ratio of the two compounds to be separated is not very large, so it is necessary to repeat the countercurrent distribution several times. However, there is a drawback that a large-sized device is required. In addition, the pH of the aqueous solution can be adjusted to pH 7.0 to 8.
．． 5, it is difficult to control, and furthermore, some of the scopolamine and hyoscyamine, which are unstable in this p)I range, decompose into toxic compounds during the long-term distribution process. , not only does this decomposition product need to be completely separated afterwards, but also the low recovery rate of side compounds is a drawback.

In view of the fact that the conventional separation method for scopolamine and hyoscyamine had many drawbacks as mentioned above, the present inventors conducted repeated research to find a more advantageous separation method, which is detailed below. The present invention has been completed.

First, an overview of the method for separating scopolamine and hyoscyamine according to the present invention will be described. In this method, a plant extract containing scopolamine and hyoscyamine is
, in an aqueous solution state of 0 or less, contact with a synthetic polymer adsorbent having a giant network structure, collect scopolamine from the non-adsorbed part and the part to be eluted by washing with water, and elute the hyoscyamine adsorbed on the synthetic polymer adsorbent. It is characterized by obtaining hyoscyamine.

Scopolamine and hyoscyamine, which can be separated by the method of the present invention, can be extracted from extracts obtained by treating plants containing tropane alkaloids by any conventional method such as bending, purified products thereof, and other sources. Non-limiting subcompounds in substances containing scopolamine and hyoscyamine, but in the following description the case will be described in which an unpurified tropane alkaloid-containing plant extract obtained by conventional methods is treated.

Processing of products with few impurities, such as intermediate purified products, can be carried out more easily and efficiently.

The material to be treated is an aqueous solution having a concentration of about 1 to 30% and a pH of 7.0 or less, preferably uH 3.0 to 4.5. 1) For the 11 adjustment, mineral acids such as hydrochloric acid and sulfuric acid or organic acids such as citric acid and oxalic acid can be used. When a tropane alkaloid-containing plant is extracted with water, the resulting extract can be directly subjected to separation treatment by simply adjusting the concentration and pH. When extraction is performed with a water-containing organic solvent, the residual liquid after distilling off the organic solvent from the extract is used. When the pH is within the above range, there is a large difference in affinity between scopolamine and hyoscyamine for the adsorbent, and chromatographic separation of the two components becomes possible. In alkaline conditions, both hyoscyamine and scopolamine are adsorbed to approximately the same extent, so although it can be used for purification to separate some of the other extracted components, it is not possible to separate the two desired components. Further, it is not preferable to make the pH pH less than 3, since this increases the amount of impurities adsorbed and lowers the purity of the hyoscyamine fraction.

The synthetic polymer adsorbent having a giant network structure used for separation treatment is a non-polar to intermediate polar adsorbent made of styrene-divinylbenzene copolymer or polyacrylic acid ester, and preferably has a specific surface area of about 300～
800n2/g @ adherent, pore volume 0.6-1.4m
l/g adsorbent, with an average pore radius of 30 to 100 pores. Specific examples of such synthetic polymer adsorbents include:
Amber Ray) XAD-2, XAD-7 (Rohm and Haas product), Diaion HP-UO1 20,
21, 40 (Mitsubishi Kasei product), Revachit 0C-
1031 (Bayer product), but is not limited to these adsorbents. (which can be adsorbed) can be used.

The amount of adsorbent used for treatment is determined depending on the amount of hyoscyamine in the liquid to be treated (or depending on the amount of adsorbent prepared and the concentration of hyoscyamine in the liquid to be treated). Accordingly, determine the amount of processing for − times.) Although it depends on the ratio of sufpolamine to hyoscyamine in the liquid to be treated and the performance of the adsorbent, in many cases, in order to separate the sulfoporamine to hyoscyamine component ratio to 5% or less, it is necessary to It is desirable that the amount of hyoscyamine in the treatment liquid is about 7 to 12 g per adsorbent 1e.

The method of bringing the adsorbent into contact with the liquid to be treated is arbitrary;
In consideration of operability, processing efficiency, etc., it is preferable to fill a column with the absorbent and feed the liquid to be treated therein by the upward method or the descending method. In this case, it is desirable that the liquid passing rate is sv (space velocity) of 4 per hour or less. If the flow rate is too high, some of the hyoscyamine may be eluted in the next water washing step and mixed into the sufboramine fraction.

When the liquid to be treated is passed through the adsorbent column as described above, the hyoscyamine adsorbed by the adsorbent remains near the inlet of the column, while the sufpolamine moves toward the column outlet while repeating adsorption and desorption. However, most of it exits the column along with the liquid passing through the column.The sufboramine remaining in the column is also absorbed by an appropriate amount of water (approximately 2 to 8 times the volume of the adsorbent).
By washing the column with hyoscyamine, most of the hyoscyamine can be eluted while remaining in the column. Therefore, when the liquid to be treated that has passed through the column and the washing water are combined, there are 95% of the sufporamine in the liquid to be treated.
More than % has been recovered. However, these two fractions also contain impurities such as water-soluble saccharides, and are purified as necessary to obtain purified sulforamine.

On the other hand, hyoscyamine retained on the adsorbent has a water content of 5
Water content methanol of about 0-60%, water content 35-45%
When a water-containing hydrophilic organic solvent such as water-containing ethanol is passed through the column, it easily adheres to the skin, and more than 95% of the hyoscyamine in the liquid to be treated is recovered in the eluent. In addition, during the desorption process of hyoscyamine, there are some impurity extract components that elute later than hyoscyamine, so by being careful not to use more than necessary amount of desorption solvent, some impurities can be separated at the same time as desorption. It is possible to carry out purification.

According to the separation method of the present invention as described above, as long as the processing conditions are appropriate, both the sufpolamine fraction and the hyoscyamine fraction have a high proportion of unseparated components of 5%. % (vs. main component), an excellent separation is achieved. Furthermore, if the sulforamine fraction or hyoscyamine fraction that retains the traces of the sulfuric acid component is subjected to the separation treatment according to the present invention once if necessary, it becomes substantially free of the sulfuric acid component.

The separation method of the present invention achieves an extremely high degree of separation in a single treatment, so not only does the time required for separation be shorter, but the equipment is smaller and more compact than self-flow distribution treatment. It is easy to understand and operate, and since it is processed in an acidic solution, there is no risk of producing toxic decomposition products of tropane alkaloids, making it easy to purify after treatment.
It is advantageous over conventional separation methods in many respects.

The present invention will be explained below with reference to Examples. Note that sulforamine and hyoscyamine were quantitatively determined on each side by gas chromatography.

Example 1 The process of extracting Zuboisha-style dried leaves IK8 with 10C of water made acidic to pi-13 with sulfuric acid was repeated three times to obtain a total of 26.5e of extract liquid, which was added to 2. It was concentrated under reduced pressure to IC. The obtained concentrate contained 15.3 g of sufboramine and 6.4 g of hyoscyamine.

Separately, six adsorbent columns filled with synthetic polymer adsorbent Amberly) The above concentrated solution in the indicated amount was passed through the column at 5V=2/Hr in a descending manner.Then, the column was washed with 500ml of water, and the washing solution was combined with the liquid to be treated that had passed through the column (sufboramine On the other hand, 500 ml of water-containing methanol containing 40% water was flowed through the washed column at 5V=2/Hr to elute hyoscyamine (hyoscyamine fraction).

Table 1 shows the results of quantifying sufboramine and hyoscyamine in the obtained sufboramine and hyoscyamine fractions to examine the degree of separation.

Example 2 Water-containing methanol 20Q containing 10% water was added to Zuboisha-style dried leaves 2, and the mixture was extracted under reflux for 3 hours. The same extraction process was repeated two more times to obtain a total of 54.3e of extract liquid, which was heated under reduced pressure to distill off methanol to obtain 4.5e of concentrated liquid.

Add 10% sulfuric acid to this concentrated solution to make r+H 3.1), add 10e of water, filter the resulting precipitate, and the resulting clear solution contains 27.5 g of sufboramine and 7.5 g of hyoscyamine. It contained.

The above clear liquid was mixed with a synthetic polymer adsorbent, Diaion HP-
SV in 20 columns (1,211:; diameter 6 cm)
= 2, (1/Hr) The column was washed with 6C water, and the washing liquid was combined with the liquid to be treated that had passed through the column, and the liquid was concentrated under reduced pressure until the liquid volume reached IC. fraction).On the other hand, the column after washing is
Water-containing methanol 6e containing 40% water is S = 1.0
/Hr to elute hyoscyamine. The obtained eluate was concentrated under reduced pressure to obtain IC (hyoscyamine fraction).

The results of quantifying sufvoramine and hyoscyamine in the obtained sufpolamine and hyoscyamine fractions were as follows.

Sufporamine fraction Sufboramine 27.1g (recovery rate 99%) Hyoscyamine 0.2g Hyoscyamine fraction Sufpolamine 0.3g Hyoscyamine 7.2g (recovery rate 96%) Next, aqueous ammonia was added to the entire amount of the sufboramine fraction and 11F1 7.
7, and liquid-liquid countercurrent distribution using chloroform 1e was repeated three times. Remove the chloroform layer,
After dehydration with anhydrous sodium sulfate, chloroform was distilled off in a vacuum mortar to obtain purified sufboramine (purity 9).
9.0%) was obtained.

Similarly, the hyoscyamine fraction whose p1 was adjusted to 8.0 with aqueous ammonia was purified by liquid-liquid countercurrent distribution using chloroform, and 9.6 g of purified hyoscyamine (purity 74.0%) was obtained. Obtained.

Agent Patent Attorney San Itai

Claims (2)

[Claims] (1) A plant extract containing scopolamine and hyoscyamine is brought into contact with a synthetic polymer adsorbent having a giant network structure in an aqueous solution state with a pH of 7.0 or less, and scopolamine is extracted from the non-adsorbed part and the part eluted by washing with water. Collect,
A method for separating scopolamine and hyoscyamine, which comprises eluting hyoscyamine adsorbed onto the synthetic polymer adsorbent to obtain hyoscyamine. (2) Synthetic polymer adsorbent has a specific surface area of 300 to +113
(l m27 g absorption body, pore volume 0.6-1.4
ml/g absorption: 11 bodies, average pore radius: 30 to 100 people.